While the etiology and treatment of COPD is complex and remains somewhat poorly defined, recent studies focusing on the peripheral consequences of COPD have begun to define the mechanisms responsible for the detrimental impact on the cardiovascular system and skeletal muscle which occur with this disease. Skeletal muscle dysfunction often leads to limitations in physical activity and to the subsequent development of cardiovascular disease, a major cause of morbidity in patients with COPD. One contributor to the muscle dysfunction and cachexia associated with COPD is oxidative stress, defined as an imbalance between pro and antioxidant molecular species in favor of the former. Free radical generation is a ubiquitous consequence of metabolism and it has been postulated that there maybe a mechanistic link between COPD, oxidative stress, and muscle dysfunction during exercise. However, to date no studies have attempted direct measurements of free radicals to determine the impact of oxidative stress in this disease. Thus, with an acute awareness of the importance and diversity of the potential COPD characteristics we propose a series of studies to better understand the role and source of oxidative stress in the skeletal muscle of COPD patients both with and without a cachectic phenotype. Four specific aims will address the following questions regarding COPD, skeletal muscle, and oxidative stress: Where is oxidative stress most prevalent, why does oxidative stress occur, what are the consequences of oxidative stress, and how does exercise-induced oxidative stress impact training responses in COPD? The overall hypothesis to be tested is that the shift toward greater intramuscular oxidative stress in COPD is, at least in part, responsible for the diminished mechanical efficiency, cachexia, and muscle related exercise limitation during work often associated with this disease. Specifically, by direct free radical detection using electron paramagnetic resonance (EPR) spectroscopy and antioxidant measurements in skeletal muscle and venous-arterial difference across the muscle bed, we will determine if there are COPD-related differences in the muscle and vascular compartments during exercise. With these same methods in combination with a reductionist approach we will determine the contribution of metabolism, shear stress and mechanical movement to the balance between free radicals and antioxidants within the muscle bed. Finally, we will utilize exogenous antioxidants and exercise training to directly document the impact of COPD and free radicals on NO, vascular growth factors, exercise training and the matching of blood flow to metabolism measured by a novel magnetic resonance imaging methodology. In combination these studies will provide clinically significant insight into the role of oxidative stress, skeletal muscle function, and vascular health in COPD.